Prostaglandin D₂-Induced Eosinophilic Airway Inflammation Is Mediated by CRTH2 Receptor

Abstract

Mast cell-derived prostaglandin D 2 (PGD 2 ) is one of the essential modulators of eosinophilic airway inflammation in asthma and allergic rhinitis. Two G protein-coupled receptors for PGD 2 , prostaglandin D 2 receptor (DP) and chemoattractant receptorhomologous molecule expressed on Th 2 cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD 2 -induced eosinophil mobilization in vitro. However, it has not yet been determined whether PGD 2 and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of PGD 2 in rats pretreated with systemic interleukin-5 (IL-5) injection induced marked airway eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD 2 , 11-deoxy-11-methylene-15-keto-PGD 2 , and indomethacin) demonstrated equivalent induction of BAL eosinophilia to that of PGD 2 , but a DP agonist (BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin]) or a thromboxane A 2 receptor (TP) agonist ([1S-1␣,2␤(5Z), 3␣(1E,3R*),4␣)]-7-[3-(3-hydroxy-4-(4Ј-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD 2 or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (ϩ)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,, or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD 2 . These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD 2 -related airway inflammation.

Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation

“…As we have previously reported (30), intratracheal instillation of PGD 2 in PBSexposed rats did not increase the number of eosinophils in BAL fluid. In contrast, PGD 2 , in a dose of 0.1-1 nM/animal, produced a significant increase in the number of eosinophils in BAL fluid of OVA-exposed animals (Fig.…”

“…In a previous study, we found that intratracheal PGD 2 induced a marked influx of eosinophils into the airways of rats pretreated with i.v. IL-5, but not of untreated rats (30). In the experiments reported herein, we found that PGD 2 recruited eosinophils into the airspace of allergen-exposed animals; there were, however, several differences in the responses to PGD 2 between the IL-5-pretreatment and the OVAsensitization/exposure models.…”

“…The lung tissues were paraffin embedded and 4-m sections were stained with Giemsa. A semiquantitative scoring system was used to grade the degree of eosinophil accumulation as previously reported (30). In brief, two separate investigators examined 10 bronchi in the lungs in a blinded manner, grading each bronchus from 0 (no eosinophils) to 4 (abundant eosinophilic infiltration) and the scores were averaged (0 -4).…”

Prostaglandin D2Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

“…Prostaglandin D 2 (PGD 2 ) is a well known inflammatory mediator in peripheral tissues (Matsuoka et al, 2000;Honda et al, 2003;Kabashima and Narumiya, 2003), invoking airway inflammation (Matsuoka et al, 2000;Shiraishi et al, 2005), inhibiting platelet aggregation (Yun et al, 1991), and causing peripheral vasodilatation (Soter et al, 1983;Alving et al, 1991). PGD 2 is synthesized by hematopoietic PGD synthase (HPGDS) and lipocalin-type PGDS (L-PGDS) and exerts its actions by binding to specific receptors, DP 1 or DP 2 (Kabashima and Narumiya, 2003;Nagata and Hirai, 2003).…”

Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids

“…In humans, CRTH2 is predominantly expressed by Th2 cells, eosinophils, and basophils, all known to play a key role in allergic diseases. 1 Activation of the Gi-coupled CRTH2 by PGD 2 or the selective agonist DK-PGD 2 stimulates chemotaxis of human Th2 cells, eosinophils, and basophils in vitro and in vivo, 2,3 suggesting that the CRTH2 receptor may directly mediate the recruitment of inflammatory cells in allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. CRTH2 is expressed by antigen-specific Th2 cells in allergic individuals supporting this notion that the CRTH2 receptor is important in the recruitment of Th2 in allergic diseases in humans.…”